Radiolabeled antibodies are exemplary targeted moieties that are used in a variety of diagnostic and therapeutic medical procedures. The increased specificity of monoclonal antibodies, compared to polyclonal antibodies, makes them more useful for delivering diagnostic or therapeutic agents such as radioisotopes to desired target sites in vivo. A monoclonal antibody specific for a desired type of target cells (e.g., tumor cells) may be used to deliver a therapeutic radionuclide-antibody conjugate to target cells, thereby causing the eradication of the undesired target cells. Alternatively, a monoclonal antibody having a diagnostically effective radionuclide attached thereto may be administered, whereupon the radiolabeled antibody localizes to target tissue. Conventional diagnostic procedures then may be used to detect the presence of target sites within the patient.
One method for radiolabeling proteins such as antibodies involves attachment of radionuclide metal chelates thereto. Chelates having a variety of chemical structures have been developed for this purpose. The usefulness of such chelates is dependent upon a number of factors including the stability of radionuclide binding within the chelate and the reactivity of the chelate with the desired protein. The efficiency of the radiolabeling process producing the radionuclide metal chelate is also important. Another consideration is the biodistribution of the radiolabeled antibody and catabolites thereof in vivo.
Image contrast achievable in diagnostic applications of this technology is limited by the ratio of radioactivity localized to the tumor and radioactivity associated with normal tissue. A limitation in the use of radioimmunotherapy in the treatment of cancer is dose limiting toxicity to normal organs. Biodistribution studies in mice have shown that compounds, such as radiolabeled small molecules, are rapidly cleared from the blood, taken up by the liver and excreted into the intestines. Such hepatobiliary excretion poses additional problems with respect to conventionally labeled antibodies, because antibody-chelate-radionuclide conjugates are metabolically degraded to form stable chelate-lysine adducts that show significant intestinal accumulation.
Certain peptides (e.g., somatostatin and derivatives thereof) have been employed as targeting agents to direct active agents to protein receptor-rich tumor targets. Hepatobiliary clearance of these radiolabeled peptides is also problematic. Also, radiolabeled ligand (e.g., biotin) derivatives used in pretargeting protocols have also exhibited undesirable hepatobiliary excretion.